Lung Immune Challenge Study Controlled Exposure to Inhaled Resiquimod (R848) to Study Mechanisms of Inflammation
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- Akhilesh Jha
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Change in Serum or Sputum CXCL10
研究概览
简要总结
Respiratory viral infections can be a cause of significant illness, particularly in vulnerable individuals as seen in the COVID-19 pandemic. An underactive or overactive immune response can lead to ineffective resolution of inflammation after an infection, especially in people with airway diseases such as asthma. A better understanding of immune responses to infection that does not rely on cell or animal models is crucial to help develop better treatments for lung inflammation.
An established method of studying inflammation in humans is through careful and controlled exposure (or "challenge") with a mimic of a virus to simulate an infection in a similar manner to that of a virus, but with the advantage of not causing an infection. The investigators have already developed a well-tolerated mimic of human viral infection using a sterile substance called Resiquimod (or R848). Since it does not contain living organisms there is no possibility of being infected. This has been used previously as a nasal spray to cause a mild short-lived inflammation that mimics a mild cold. This has been used safely in a range of people of different ages including those who have asthma.
There are differences however in how the nose and lungs respond to viral infections. This is particularly true in those with airway diseases such as asthma, who have cells in the airways of their lungs that respond in a different way to inflammatory triggers (such as viruses).
The current study aims to build on previous research by developing a new approach of studying inflammation in the lungs using a small volume of Resiquimod. This will be done by gently inhaling a fine mist through a mouthpiece into the lungs. Blood and phlegm samples would then be collected to assess inflammation and how well people tolerate the procedure.
详细描述
Background The initial immune response to respiratory viral infections is key to determining what kind of clinical outcome is experienced. The COVID-19 pandemic highlights the key importance of gaining a thorough understanding of these immune mechanisms.
People with chronic lung conditions such as asthma often experience more severe and prolonged symptoms in response to external triggers. This can be due to ongoing inflammation in their airways and lungs. Animal and cell models fail to accurately recapitulate the disease, which limit its usefulness in developing new treatments.
Observational human studies of asthma attacks can be useful but have several confounding factors, which significantly influence the outcomes being assessed. For example, one issue may be the significant variability in time between exposure to a pathogen to the point at which they present to hospital.
One important method for understanding mechanisms of inflammation in humans, is to perform controlled and careful exposure to an inflammatory stimulus to assess why and how differences occur between individuals. This is already established using live viral infection studies - however these studies are technically difficult, resource intensive, may make participants feel unwell for several days, and can be inconvenient for them due to the need for prolonged quarantine.
An alternative approach for studying the first line of immune defence (or "innate immunity"), is to use a mimic of a virus that binds to the same receptors as respiratory viruses such as influenza and SARS-CoV-2. The study team have already established and published this research using a nasal spray with a synthetic compound called Resiquimod (R848). It generates an inflammatory response with the release of molecules such as interferons and cytokines in the nose in a very similar manner to what we see with live viral infections. This approach has been used to demonstrate differences in immune responses between healthy individuals and people with asthma.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male or female aged between 18 and 60 years.
- •Willing and able to give informed consent for participation in the study.
- •Female participants of child-bearing potential and male participants whose partner is of child-bearing potential must be willing to ensure that they or their partner use effective contraception during the study.
- •Clinically acceptable laboratory measurements and ECG at enrolment.
- •Ability to expectorate sputum.
- •Optional additional swab for SARS-CoV-2 testing will be collected from participants if required by local or/and national health and safety policies at the time of sampling.
- •For healthy volunteers:
- •No clinical history of asthma
- •Normal baseline spirometry i.e. FEV1/Forced Vital Capacity (FVC) ratio z-score greater than the lower limit of normal.
- •For volunteers with asthma:
- •Physician-diagnosed mild to moderate asthma which is not poorly controlled as evidenced by an Asthma Control Questionnaire (ACQ-5) score of ≤1.
- •They are permitted to be on inhaled corticosteroids (ICS), long-acting beta agonist (LABA) and long-acting muscarinic antagonists (LAMA).
- •Pre-bronchodilator FEV1 ≥70% predicted.
- •Evidence of bronchial hyperreactivity as evidenced by either (i) Bronchodilator reversibility (increase FEV1 ≥12% and 200 mL); (ii) Positive methacholine challenge (PC20 < 8mg/ml), or (iii) Positive challenge test as per current CUH policy.
排除标准
- •Upper respiratory tract infection in preceding 14 days.
- •Lower respiratory tract infection in preceding 28 days.
- •Female participants who are pregnant, lactating or planning pregnancy.
- •Respiratory diseases (other than asthma where specified).
- •Significant extrapulmonary medical conditions.
- •Extreme obesity (BMI >40).
- •Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.
- •Participants who have participated in another research study involving an investigational product in the past 12 weeks.
- •No newly prescribed courses of medication including corticosteroids in the four weeks before first study dose other than mild analgesia, vitamins, and supplements.
- •Smoking tobacco or vaping products in previous 6 months.
- •Smoking history of >5 pack years.
研究组 & 干预措施
R848 0.1 μg/mL
Inhaled Resiquimod (R848) 0.1 μg/mL
干预措施: R848 (Drug)
R848 1.0 μg/mL
Inhaled Resiquimod (R848) 1.0 μg/mL
干预措施: R848 (Drug)
R848 10 μg/mL
Inhaled Resiquimod (R848) 10 μg/mL
干预措施: R848 (Drug)
R848 100 μg/mL
Inhaled Resiquimod (R848) 100 μg/mL
干预措施: R848 (Drug)
Saline
Inhaled Saline
干预措施: Saline (Drug)
Asthma volunteers inhaled R848
Highest tolerated dose inhaled R848 in healthy volunteers to be given to volunteers with asthma
干预措施: R848 (Drug)
Asthma volunteers inhaled saline
Inhaled saline to be given to volunteers with asthma
干预措施: Saline (Drug)
结局指标
主要结局
Change in Serum or Sputum CXCL10
时间窗: 3 weeks from screening visit until 24 hours after inhaled R848 challenge
Change in CXCL10 in serum or induced sputum before and after inhaled R848
次要结局
- Change in FEV1(Change in FEV1 at 1, 4, 8, 24 and 48 hours after single ascending dose inhaled R848 or saline)
- Change in Temperature(Change in temperature (degrees celsius) at 1, 4, 8, 24 and 48 hours after single ascending dose inhaled R848 or saline)
- Change in Pulse Rate(Change in Pulse Rate at 1, 4, 8, 24 and 48 hours after single ascending dose inhaled R848 or saline)
- Change in Systolic Blood Pressure(Change in systolic blood pressure at 1, 4, 8, 24 and 48 hours after single ascending dose inhaled R848 or saline)
- Change in Peripheral Eosinophil Counts(Change in peripheral eosinophil counts at 4, 24 and 48 hours after single ascending dose inhaled R848 or saline)
- Change in Peripheral Lymphocyte Counts(Change in peripheral lymphocyte counts at 4, 24 and 48 hours after single ascending dose inhaled R848 or saline)
- Change in Serum CRP(Change in serum CRP at 4, 24 and 48 hours after single ascending dose inhaled R848 or saline)
研究者
Akhilesh Jha
MRC Clinician Scientist
Cambridge University Hospitals NHS Foundation Trust